A method for targeting pharmaceutically active principle in total knee replacement

Abstract

A method of treating or managing pain or inflammation in a patient following a total knee replacement (TKR) by administering to the knee joint of said patient biodegradable drug delivery compositions. The biodegradable drug composition comprises a triblock copolymer containing a polyester and a polyethylene glycol and a diblock copolymer containing a polyester and an end-capped polyethylene glycol, as well as an NSAID.

Description

[0001] A METHOD FOR TARGETING PHARMACEUTICALLY ACTIVE PRINCIPLE IN TOTAL KNEE REPLACEMENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a method for treating or managing pain or inflammation in a patient following a total knee replacement (TKR), particularly first-time TKR patients, by administering a biodegradable drug delivery composition comprising an NSAID, a triblock copolymer containing a polyester and a polyethylene glycol and a diblock copolymer containing a polyester and one end-capped polyethylene glycol.

[0004] BACKGROUND OF THE PRESENT INVENTION

[0005] Osteoarthritis (OA) is the most common type of joint disease, affecting more than 20 million individuals in the United States alone. OA is a degenerative disorder arising from the biochemical breakdown of articular (hyaline) cartilage in synovial joints. Although research into disease modifying osteoarthritis drugs have tried to find non-surgical solutions to this troublesome condition, they have been largely unsuccessful, leaving total knee replacement (TKR) surgery as the most viable treatment option.

[0006] There were approximately 680,150 total knee replacements (TKR) performed in the US in 2014, and this number is projected to grow 85% to 1.26 million procedures per year by 2030. [M. Sloan, A. Premkumar, N.P. Sheth, Projected Volume of Primary Total Joint Arthroplasty in the U.S., 2014 to 2030, The Journal of bone and joint surgery. American volume 100(17) (2018) 1455-1460.] Safe and effective management of pain following this invasive surgery remains a major clinical challenge, and directly influences length of hospital stay, rehabilitation success, and overall patient recovery time. Total excision of cartilage and resection of bone, cementing of large prosthetic implants to bone, and bruising and soreness of associated soft tissues are accompanied by excessive levels of pain, inflammation, swelling and bleeding.

[0007] Although TKR is widely considered the gold standard in treatment of end stage knee pathologies, it is believed that approximately 20% of TKR patients experience chronic pain, complications, and poor clinical outcomes (Scott, C. E., Howie, C. R., MacDonald, D., and Biant, L. C. (2010) Predicting dissatisfaction following total knee replacement: a prospective study of 1217 patients. The Journal of bone and joint surgery. British volume 92, 1253-1258). These poor results likely arise from poorly controlled post-operative pain and inflammation which often necessitate a revision surgery that profoundly impairs quality of life, adds significant socio-economic burden due to its complexity, cost, and high complication rate.

[0008] While the trauma associated with TKR surgery has changed little over time, improvements in the standard of care for acute care analgesia with multimodal approaches have resulted in decreased length of hospital stay and earlier patient discharges, approaching same-day. Unfortunately, once at home without hospital monitoring and support, patients typically experience intense pain and inflammation after peri-operative analgesia wears off, with most patients requiring opioid analgesia for at least 6 weeks. [E.C. Sun, B.D. Darnall, L.C. Baker, S. Mackey, Incidence of and Risk Factors for Chronic Opioid Use Among Opioid-Naive Patients in the Postoperative Period, JAMA Intern Med 176(9) (2016) 1286-93; R. Fuzier, I. Serres, R. Bourrel, A. Palmaro, J.L. Montastruc, M. Lapeyre-Mestre, Analgesic drug consumption increases after knee arthroplasty: a pharmacoepidemiological study investigating postoperative pain, Pain 155(7) (2014) 1339-45],

[0009] Consequently, TKR surgery has the highest requirement for opioid prescriptions across all surgical procedures [M. Mundkur, Background and Rationale for the Development of Opioid-Sparing and Opioid-Replacement Drugs, Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC), FDA, 2018] and also serves as a gateway for opioid addiction in 15% of TKR patients [P. Pharmaceuticals, Exposing a silent gateway to persistent opioid use: A choices matter status report, 2018], which will represent nearly 144,000 Americans in 2021 alone (calculated from data in [M. Sloan, A. Premkumar, N.P. Sheth, Projected Volume of Primary Total Joint Arthroplasty in the U.S., 2014 to 2030, The Journal of bone and joint surgery. American volume 100(17) (2018) 1455-1460]).

[0010] Inflammation is the body’s response to injury and is an intrinsically beneficial event that leads to the restoration of tissue structure and physiological function. The usual outcome of an acute inflammatory process is successful resolution and repair of tissue damage. Alternatively, failure of acute inflammation to resolve (or be correctly managed) may predispose to poor wound healing, arthrofibrosis, pain and loss of function. [E. Ricciotti, G.A. FitzGerald, Prostaglandins and inflammation, Arteriosclerosis, thrombosis, and vascular biology 31(5) (2011) 986-1000],

[0011] Prostaglandins (PG) play a key role in the generation of the inflammatory response. [E. Ricciotti, G.A. FitzGerald, Prostaglandins and inflammation, Arteriosclerosis, thrombosis, and vascular biology 31(5) (2011) 986-1000] They are generated from arachidonate by the action of cyclooxygenase isoenzymes COX-1 and COX-2, and their biosynthesis is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs), including those selective for inhibition of COX- 2. PG production is generally very low in non-inflamed tissues, but their biosynthesis is significantly increased in inflamed tissue. PGs contribute to the development of acute inflammation, recruitment of leukocytes, and infiltration of immune cells. During inflammation, Prostaglandin E2 (PGE2) is of particular interest because it is involved in all processes leading to the classic signs of inflammation: redness, swelling and pain. Cyclooxygenase-2 (COX-2) appears to be the dominant driver of prostaglandin formation in inflammation, and its expression in inflamed tissues provided a rationale for the development of NSAIDs designed to selectively inhibit COX-2. Thus, COX-2 inhibitors were developed, including celecoxib, and are used in a broad range of clinical conditions for pain management. [M.H. Zemmel, The role of COX-2 inhibitors in the perioperative setting: efficacy and safety-a systematic review, AANA J 74(1) (2006) 49-60] Celecoxib was first approved by the FDA as an oral capsule formulation, Celebrex, in 1998 (Pfizer, 1998). It is indicated for the relief of osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis, acute pain, and dysmenorrhea. However, the use of oral NSAIDs can have both short- and long-term adverse consequences. In the short-term, COX- 2 inhibitors may increase the risk of post-operative bleeding by adversely interacting with drugs used for prophylaxis of deep vein thrombosis (DVT). Additionally, there is increased risk of cardiovascular, gastrointestinal, and hypertensive complications associated with longer term systemic exposure to COX-2 inhibitors. [L.G. Howes, Selective COX-2 inhibitors, NSAIDs and cardiovascular events - is celecoxib the safest choice? Therapeutics and clinical risk management 3(5) (2007) 831-45; D. Clemett, K.L. Goa, Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain, Drugs 59(4) (2000) 957-80],

[0012] Thus, there is still a need in this art to deliver non-opioid, pharmaceutically active principles, in particular for the management of pain and inflammation, directly into the knee joint and increase the duration of local effect through sustained delivery, while limiting systemic exposure and obviating the need for chronic oral administration.

[0013] Thus, there is still a need to provide methods of managing or treating pain and / or inflammation following TKR. There is also a need to improve patient recovery following TKR.

[0014] These and other objects are achieved by the present invention as evidenced by the summary of the invention, the description of the preferred embodiments and the claims. SUMMARY OF THE INVENTION

[0015] The present invention provides a method for treating or managing pain or inflammation in a patient following a total knee replacement (TKR) which comprises administering to the knee joint of said patient a biodegradable drug delivery composition comprising:

[0016] (a) a biodegradable triblock copolymer having the formula:

[0017] PLAv-PEGw-PLAx wherein v and x are the number of repeat units ranging from 24 to 682 and w is the number of repeat units ranging from 4 to 273 and v=x or v x;

[0018] (b) a biodegradable diblock copolymer having the formula: mPEGy-PLAzwherein y and z are the number of repeat units with y ranging from 3 to 68 and z ranging from 7 to 327, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 3:2 to 1 :19 in said biodegradable drug composition the and (c) a nonsteroidal antiinflammatory drug (NSAID).

[0019] Preferably, said patient has not previously had TKR, i.e., the present invention is directed to a method of pain or inflammation treatment or management in patients having a first TKR with the biodegradable drug delivery system.

[0020] In a further aspect, the invention provides a method for treating or managing pain or inflammation in a patient following a TKR which comprises administering to the knee joint of said patient a biodegradable drug delivery composition comprising:

[0021] (a) a biodegradable triblock copolymer having the formula:

[0022] PLAv-PEGw-PLAxwherein v and x are the number of repeat units ranging from 24 to 682 and w is the number of repeat units ranging from 4 to 273 and v=x or v x;

[0023] (b) a biodegradable diblock copolymer having the formula: mPEGy-PLAzwherein y are the number of repeat units with y ranging from 3 to 68 and z ranging from 7 to 327, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 3:2 to 1 :19 in said biodegradable drug composition the and (c) a nonsteroidal anti-inflammatory drug (NSAID), wherein said patient has not previously had a TKR.

[0024] Typically, said NSAID is present in said formulation in an amount of 1% to 85% w% / w%, 1% to 60% (wt% / wt%), or 10% to 60% (wt% / wt%), or 10% to 30% (wt% / wt%), or 10% to 20% (wt% / wt%), or about 15% (wt% / wt%) of the total composition.

[0025] In an embodiment, the polyethylene glycol chain in the triblock copolymer and / or the diblock copolymer has a molecular weight ranging from 300 Da to 12 kDa, or 1 kDa to 8 kDa, or 1 kDa to 5 kDa, or 1 kDa to 2 kDa. In one embodiment the polyethylene glycol chain in the triblock and / or the diblock copolymer has a molecular weight of from 1.5 to 2.5 kDa. In one embodiment the polyethylene glycol chain in the triblock and / or the diblock copolymer has a molecular weight of about 2 kDa.

[0026] In an embodiment, the lactic acid to ethylene oxide molar ratio for the triblock copolymer is from 1.6 to 7.2 or 1 .6 to 5.0 or 1.6 to 3.0, or about 2.0.

[0027] In an embodiment, the lactic acid to ethylene oxide molar ratio for the diblock copolymer is from 1.6 to 7.2 or 1 .6 to 5.0 or 1.9 to 4.8, or 1.9 to 3.0, or about 2.4.

[0028] In one embodiment, the lactic acid to ethylene oxide molar ratio is 1.6 to 7.2 in the triblock copolymer and 1.9 to 4.8 in the diblock copolymer.

[0029] Typically, the degree of polymerization in the triblock copolymer is from 92 to 135 and the degree of polymerization in the diblock copolymer is from 91 to 180, or the degree of polymerization in the triblock copolymer is 95 to 130 and the degree of polymerization in the diblock copolymer is from 95 to 175, or the degree of polymerization in the triblock copolymer is 99 to 132 and the degree of polymerization in the diblock copolymer is from 95 to 175, or the degree of polymerization in the triblock copolymer is 100 to 170 and the degree of polymerization in the diblock copolymer is from 115 to 195.

[0030] In one embodiment, the triblock copolymer is present in an amount of 2% to 45% (wt% / wt%), or 6% to 24% (wt% / wt%), or 6% to 15% (wt% / wt%), 6% to 10% (wt% / wt%), or about 8% (wt% / wt%) of the total composition. In one embodiment, the diblock copolymer is present in an amount of 8% to 50% (wt% / wt%), or 12% to 40% (wt% / wt%), or 20% to 40% (wt% / wt%), or about 32% (wt% / wt%) of the total composition.

[0031] In one embodiment, the triblock copolymer is present in an amount of 6% to 24% (wt% / wt%) and the diblock copolymer is present in an amount of 12% to 40% (wt% / wt%) of the total composition. Typically, the total polymer content ranges from 20% to 50% (w% / w%) or 30% to 50% (w% / w%), or about 40% (w% / w%) of the total composition.

[0032] In one embodiment, the total polymer content ranges from 30% to 50% (w% / w%) of the total composition and the NSAID is present in an amount of 10% to 20% (w% / w%) of the total composition.

[0033] Preferably, the composition further comprises a pharmaceutically acceptable vehicle. Typically, the pharmaceutically acceptable vehicle is a biocompatible organic solvent. The biocompatible organic solvent may be selected from the group of: benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl- 2-pyrrolidone, N-methyl-2-pyrrolidinone(NMP), pyrrolidone-2, tetraglycol, triacetin, tributyrin, tripropionin (tripro) and mixtures thereof. In one embodiment the solvents are DMSO, tripo, NMP and mixtures thereof, preferably DMSO.

[0034] In one embodiment the NSAID may be at least one of etofenamate, celecoxib, apricoxib, rofecoxib, nabumetone, benorilate, etoricoxib, ampiroxicam, aminophemazone, valdecoxib, acetominophen, bufexamac, nimesulide, parecoxib, mefenamic acid, dexibuprofen, ibuprofen, flurbiprofen, aspirin, dexketoprofen, diclofenac, diflunisal, etodolac, fenoprofen, firocoxib, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, loxomac, lumiracoxib, meclofenamic acid, meloxicam, naproxen, naprosyn, nimalox, oxaporozin, piroxicam, salsalate, sulindac, tenoxicam, tolfenamic acid, and ropivicaine. Preferably the NSAID is celecoxib.

[0035] In one embodiment, the composition comprises celecoxib in an amount of 13% to 17% (wt% / wt%), the triblock copolymer in an amount of 7% to 9% (wt% / wt%), the diblock copolymer in an amount of 30% to 34% (wt% / wt%), and dimethyl sulfoxide in an amount of 43% to 47% (wt% / wt%) of the total composition.

[0036] In one embodiment, the formulation of said biodegradable drug composition is made by mixing the triblock copolymer with the diblock copolymer in a biocompatible organic solvent to form a triblock copolymer and diblock copolymer mixture, and the NSAID is added to said triblock copolymer and diblock copolymer mixture. In one embodiment, the solvent is evaporated off.

[0037] In one embodiment, said triblock copolymer and diblock copolymer mixture is further exposed to an aqueous liquid to form a solid bolus.

[0038] Typically, the composition is administered to said patient in a volume of 0.1 to 6 ml or 2 to 5 mL or 3 to 4 mL. Typically, the composition has concentration of celecoxib of from about 150 mg / mL to about 200 mg / mL, or from about 170 to about 190 mg / mL.

[0039] Typically, the maximal celecoxib plasmatic concentration reached after a single administration of the composition is less than 200 ng / mL, optionally less than 180 ng / mL, optionally less than 160 ng / mL 24 hours after the TKR.

[0040] Typically, a therapeutically effective concentration of the NSAID is released for a period of at least 4 weeks, preferably at least 6 weeks, preferably at least 8 weeks after the TKR.

[0041] Typically, the composition is a liquid that can be injected into the knee joint or are solid particles that can be injected into the knee joint or are rod implants or spatial formulations.

[0042] Optionally, the method further comprises the administration of standardized multimodal analgesia.

[0043] The standardized multimodal analgesia may comprise two or more active pharmaceutical ingredients selected from bupivacaine, ropivacaine, lidocaine, acetaminophen, methocarbamol, pregabalin, gabapentin, ketamine, morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, tramadol, tapentadol, a nerve block and dexamethasone. In one embodiment, the standardized multimodal analgesia comprises bupivacaine hydrochloride, acetaminophen and methocarbamol.

[0044] The two or more active pharmaceutical ingredients may be administered at the same time as the biodegradable drug delivery composition, or separately or sequentially.

[0045] Optionally, bupivacaine is administered via periarticular infiltration using a mixture of 0.25% bupivacaine with epinephrine (1 :200,000) and 0.25% bupivacaine without epinephrine at a ratio of 2:1 respectively for subjects weighing less than 80 kg, and at a ratio of 3:1 respectively for subjects weighing more than 80 kg at 1 mL / kg up to 90 mL. The standardized multimodal analgesia typically comprises an opioid, optionally wherein the opioid is selected from morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, tramadol, tapentadol, and combinations thereof or wherein the opioid is morphine and / or oxycodone.

[0046] In one embodiment mean cumulative opioid consumption of the patient is reduced relative to a patient receiving only the standardized multimodal analgesia comprising opioid, optionally wherein opioid consumption is reduced from 2 weeks to 90 days after the TKR, or over 2 weeks, or 4 weeks, or 6 weeks, or 8 weeks or 12 weeks, or 90 days after the TKR.

[0047] In one embodiment, when analyzing all patients, there is from a 15% to 20% reduction in cumulative opioid consumption 90 days after the TKR. In one embodiment, for patients who have had no previous TKR, there is from a 25% to 30% reduction in cumulative opioid consumption 90 days after the TKR.

[0048] In one embodiment the daily opioid consumption of the patient is reduced relative to a patient receiving only the standardized multimodal analgesia comprising opioid, optionally wherein the daily opioid consumption is reduced from 2 weeks to 90 days after the TKR, or over 2 weeks, or 4 weeks or 6 weeks, or 12 weeks or 90 days after the TKR.

[0049] Typically, the mean cumulative opioid consumption or daily opioid consumption is measured in Morphine Milligram Equivalents (MME).

[0050] In one embodiment there is a reduction in Area Under the Curve (AUC) of Numeric Rating Score (NRS) pain of the patient at 3 days, 7 days, 2 weeks, 6 weeks or 90 days after the TKR relative to a patient receiving only the standardized multimodal analgesia. Optionally, the reduction is calculated based on the least squares mean of AUC of NRS. In one embodiment, the reduction in least squares mean of AUC of NRS pain of the patient relative to a patient receiving only the standardized multimodal analgesia may be at least 3%, optionally least 4%, optionally at least 5%, optionally at least 6%. In patients with no previous TKR, the reduction in least squares mean of AUC of NRS pain of the patient relative to a patient receiving only the standardized multimodal analgesia may be at least 8%, optionally at least 9%, optionally at least 10%, optionally at least 12%, optionally at least 14%, optionally at least 16%. In one embodiment the AUC of Numeric Rating Score (NRS) pain is statistically adjusted for consumption of opioids.

[0051] In one embodiment there is a reduction in the least squares mean of the Visual Analog Scale (VAS) for pain of the patient at 2 weeks, 6 weeks or 90 days after the TKR relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the reduction is at least an 10%, optionally at least a 20% difference in least squares mean of the VAS.

[0052] In one embodiment the patient has a reduced time period to a knee range of motion of between 100 and 110 degrees relative to a patient receiving only the standardized multimodal analgesia.

[0053] In another embodiment the patient has an improved knee range of motion (ROM) relative to a patient receiving only the standardized multimodal analgesia between 1 week and 3 months after the TKR or at 1 week, or at 2 weeks, or at 3 weeks, or at 6 weeks, or at 12 weeks after the TKR, optionally wherein there is a 5 to 10% improvement of ROM relative to a patient receiving only the standardized multimodal analgesia at 3 months after the TKR.

[0054] In one embodiment there is a reduction in effusion of the knee of the patient measured as the percentage difference in circumference of the knee which has had a TKR relative to the contralateral knee and relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the measurement is made at 2 weeks, or at 6 weeks or at 3 months after the TKR.

[0055] In a further embodiment there is an improvement in mobility of the patient as measured by the Timed Up and Go Test relative to a patient receiving only the standardized multimodal analgesia, wherein the Timed Up and Go Test measures the time it takes for the patient to stand up, walk a distance of 3 meters (10 feet), turn, walk back and sit down again, optionally wherein the Timed Up and Go Test result is measured at 2 weeks or at 6 weeks or at 3 months after the TKR.

[0056] In one embodiment, the Physical Component Summary score of the Short Form 12 (SF-12v2) Health Survey is increased by at least 15% or at least 30% from the value for a patient receiving only the standardized multimodal analgesia.

[0057] In an additional embodiment the health status of a patient as measured by the EuroQoL 5D (EQ-5D-5L) index 2 weeks after the TKR is improved relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the index increases by at least 70, or at least 85 from the value for a patient receiving only the standardized multimodal analgesia. In an embodiment of the invention where patients have not had a previous TKR, the index 2 weeks after the TKR may increase by at least 150, or at least 170 from the value for a patient receiving only the standardized multimodal analgesia.

[0058] In one embodiment, the Knee Society Score 2011 (KSS2011) of a patient as measured 2 weeks after the TKR is improved relative to a patient receiving only the standardized multimodal analgesia, optionally wherein there is at least a 30%, or at least a 40%, or at least a 50% increase in the KSS2011 patient satisfaction and / or functional activities score of a patient relative to a patient receiving only the standardized multimodal analgesia. For patients who have not previously had a TKR, there is there is typically at least a 40%, or at least a 50%, or at least a 60% increase in the KSS2011 patient satisfaction and / or functional activities score of a patient relative to a patient receiving only the standardized multimodal analgesia.

[0059] In one embodiment said biodegradable drug delivery composition is taken up by syringe for administration and injected into said knee joint or manually formed in into a solid bolus by exposing the formulation to aqueous liquid and manual placement into the knee joint.

[0060] In one embodiment said biodegradable drug delivery composition is subjected to a mechanical challenge. Typically, said mechanical challenge is obtained by internal structures of the joints, articulation, weight bearing and / or by synovial fluid pressure.

[0061] In a further aspect, the invention provides a composition for use in a method as defined above.

[0062] With the method for treatment or management of pain or inflammation following TKR the biodegradable drug delivery composition may be morselized by causing the biodegradable drug delivery formulation to be subjected to a mechanical challenge such as those obtained by internal structures of the knee joint, articulation, weight bearing and / or by synovial fluid pressure. In this method the biodegradable drug delivery formulation is broken into pieces (i.e. , morselized).

[0063] Other aspects and embodiments are set forth below, or will readily arise from the following description of the preferred embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Fig. 1 shows the plasma concentration of celecoxib over time.

[0065] Fig. 2 shows the VAS Least Squares mean pain score over a 90 day period for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (solid line) and patients administered MMA alone (dashed line) for all patients in the phase 2 clinical trial.

[0066] Fig. 3 shows the range of motion (ROM) in degrees versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (solid line) and patients administered MMA alone (dashed line) for all patients in the phase 2 clinical trial.

[0067] Fig. 4 shows the percentage difference in AUG NRS pain score for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) and patients administered MMA alone for those patients who have not previously had a TKR, statistically adjusted for consumption of opioids.

[0068] Fig. 5 is a graph showing mean cumulative opioid consumption in Morphine Milligram Equivalents (MME) versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (black circles) and patients administered MMA alone (white circles) for all patients (top panel) and for patients with no previous TKR (bottom panel).

[0069] Fig. 6A is a graph showing the knee range of motion (ROM) in degrees versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (black circles) and patients administered MMA alone (white circles) for all patients (top panel) or only those patients who have not previously had a TKR (bottom panel) in the phase 3 clinical trial.

[0070] Fig. 6B is an expanded version of the bottom panel of Fig. 6A showing the ROM for patients who have not previously had a TKR over the time period of 2 to 12 weeks. The benchmark ROM required for rehabilitation is shown with a dashed line.

[0071] Fig. 6C provides a schematic for how the ROM is measured. Fig. 7 is a graph showing the knee effusion (percentage difference in circumference from contralateral knee) versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (black circles) and patients administered MMA alone (white circles) for all patients (top panel) or only those patients who have not previously had a TKR (bottom panel).

[0072] Fig. 8 is a graph showing the Timed-Up-and-Go Test (TUG) duration versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (squares) and patients administered MMA alone (circles) for all patients (top panel) or only those patients who have not previously had a TKR (bottom panel).

[0073] DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] As used herein the term “biodegradable” means that the triblock and diblock copolymers will after a period of time, erode, degrade or morselize in vivo to form smaller nontoxic components.

[0075] The term “animals” encompasses all members of the Kingdom Animalia.

[0076] Mammals, as used herein, encompasses any group of vertebrates the females of which have milk-secreting glands, including man. Examples of mammals include, but are not limited to cats, dogs, humans, pigs, horses, cattle, apes, chimpanzees and the like.

[0077] “Active principle” or “Active Pharmaceutical ingredient” means a drug or medicine for treating or managing a condition or disease, or symptoms thereof, and in the present application in particular pain or inflammation following TKR. Thus active principles, drugs and medicines are used interchangeably. The term drug or active principle as used herein includes without limitation physiologically or pharmacologically active substances that act locally or systemically in the body of an animal. At least one active principle is present in the biodegradable drug composition of the invention used in the method of the present invention. More than one active principle can be used in the methods of the present invention such as a non-steroidal anti-inflammatory drug and a local anaesthetic.

[0078] Nonsteroidal anti-inflammatory drugs (NSAIDs) are a drug class for use as antipyretic, anti-inflammatory, and analgesic agents. These effects make NSAIDs useful for treating pain and inflammation after TKR. NSAIDs are typically divided into groups based on their chemical structure and selectivity: acetylated salicylates (aspirin), non-acetylated salicylates (diflunisal, salsalate), propionic acids (naproxen, ibuprofen, acetic acids (diclofenac, indomethacin), enolic acids (meloxicam, piroxicam) anthranilic acids (meclofenamate, mefenamic acid), naphthylalanine (nabumetone), and selective COX-2 inhibitors (celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib).

[0079] The term “implant” means that the drug delivery compositions are injectable, are in situ forming and are biodegradable and turn into solid implants when put in contact with aqueous liquids after injection into the intra-articular space. Thus, that the formulations that are synthesized are liquids such that they can be easily injected through a syringe without excessive force.

[0080] The term “spatial formulations” encompass any formulations that can be applied on or into the mammalian or animal body and do not necessarily have to be administered through a syringe.

[0081] As used herein “repeat units” are the fundamental recurring units of a polymer.

[0082] The reaction of a methoxy PEG polymer with lactide generates a diblock methoxy polyethylene glycol- poly(lactic acid), or mPEG-PLA copolymer. “mPEG” refers to methoxy polyethylene glycol.

[0083] As used herein polyethylene glycol, as abbreviated PEG throughout the application, is sometimes referred to as poly(ethylene oxide) or poly(oxyethylene) and the terms are used interchangeably in the present invention.

[0084] The abbreviation of “PLA” refers to poly(lactic acid). Preferably, the poly(lactic acid) is poly(D,L-Lactic Acid).

[0085] The abbreviation “T” or “TB” refers to a triblock copolymer(s), while the abbreviation “D” or “DB” refers to a diblock copolymer(s).

[0086] The term “triblock” refers, for example, to a polyester-PEG-polyester copolymer, in the present invention a poly(lactic acid)-PEG-poly(lactic acid) copolymer, also referred to as a PLA-PEG-PLA triblock copolymer. As used herein the term “synovial tissue” refers to the thin, loose vascular connective tissue that makes up, more specifically lines the interior of all joints and also the sheaths surrounding tendons such as in the hands and feet. Synovial tissue contains 2 types of synovial cells, one which secretes a viscous liquid called synovial fluid containing proteins and hyaluronic acid, and that serves as a lubricant and nutrient for the joint cartilage surfaces, and the second which act as phagocytes and clear the knee joint of debris, blood or foreign bodies.

[0087] “Synovium,” as used herein, is a membrane, also known as the synovial tissue, surrounding the joints that secretes a fluid that lubricates and provides nutrition to tissues.

[0088] As used herein “other joint tissues” include, but is not limited to articular cartilage, ligaments, meniscus, tendons, rotator cuffs and the like.

[0089] As used herein, “intra-articular” refers to the space inside of a joint between two bones, specifically to the portion of the joint contained by the joint capsule. Meaning “inside of a joint,” intra-articular may refer to the space itself or, in the case of the body’s movable joints, to any tissues or fluid found inside. Within the intra-articular space is the synovial fluid, the lubricating fluid of the joint, as well as articular cartilage, which provides a near frictionless gliding surface or cushion between the adjoining bony surfaces. Other joint types may feature ligaments in their intra-articular space that hold the two bones together. In synovial or movable joints, these tissues are extra-articular, or outside of the joint capsule.

[0090] “Targeting,” as used herein, means a method of delivering at least one pharmaceutically active principle to a mammal or animal that increases the concentration of the drug(s) in the synovial tissue relative to other parts of the body. This targeting permits the prolongation and localization of the pharmaceutically active principle with the synovial tissue.

[0091] By “morselization” is meant the act of breaking up into fragments or particles; subdivision; decentralization. It is the same as morcellation. Morselization can be used to target joints and joint cells, cartilage, ligaments, tendons, synovial fluid, rotator cuffs, menisci, or inflammatory disease (e.g., osteoarthritis, rheumatoid arthritis) or joint pain and the like through non-surgical application by intra-articular injection.

[0092] Thus, in one aspect the present invention relates to a method for treating or managing pain or inflammation in a patient following a total knee replacement (TKR) which comprises administering to the knee joint of said patient a biodegradable drug delivery composition comprising:

[0093] (a) a biodegradable triblock copolymer having the formula:

[0094] PLAv-PEGw-PLAx wherein v and x are the number of repeat units ranging from 24 to 682 and w is the number of repeat units ranging from 4 to 273 and v=x or v x;

[0095] (b) a biodegradable diblock copolymer having the formula: mPEGy-PLAzwherein y and z are the number of repeat units with y ranging from 3 to 68 and z ranging from 7 to 327, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 3:2 to 1 :19 in said biodegradable drug composition and (c) a nonsteroidal anti-inflammatory drug (NSAID).

[0096] Treating or managing pain encompasses entirely eliminating pain caused by the TKR, or reducing pain, for example reducing the intensity and / or duration of pain. The methods of the invention also treat or manage inflammation of the knee joint, i.e. they reduce or eliminate inflammation caused by the TKR.

[0097] The pain can be current pain, i.e. pain being felt at the time the patient reports. Alternatively, the pain can be recall pain which is the worst pain felt by the patient over the previous 12 hours.

[0098] Preferably, said patient has not previously had TKR, i.e., the present invention is directed to a method of pain or inflammation treatment or management in patients having a first TKR with the biodegradable drug delivery composition.

[0099] Three patient populations are described. These are: i) those who have never had either knee replaced (described as a patient who has not previously had a TKR in the present application, or as NO PREVIOUS TKR, or NO TKR), ii) those who have had a TKR in one leg, but due to some complication a revision TKR of their first TKR was needed (not enrolled in the clinical studies described in the present application) iii) those who had a prior TKR in one leg, and then underwent a second TKR in the contralateral leg (patients referred to as having had a previous TKR in our data). Thus, in the present invention no previous TKR has occurred on the treated leg. Most preferably no previous TKR has occurred on either leg, referred to hereinafter as the patient has not previously had TKR.

[0100] In a further aspect, the invention provides a method for treating or managing pain or inflammation in a patient following a TKR which comprises administering to the knee joint of said patient a biodegradable drug delivery composition comprising:

[0101] (a) a biodegradable triblock copolymer having the formula:

[0102] PLAv-PEGw-PLAx wherein v and x are the number of repeat units ranging from 24 to 682 and w is the number of repeat units ranging from 4 to 273 and v=x or v x;

[0103] (b) a biodegradable diblock copolymer having the formula: mPEGy-PLAzwherein y are the number of repeat units with y ranging from 3 to 68 and z ranging from 7 to 327, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 3:2 to 1 :19 in said biodegradable drug composition the and (c) a nonsteroidal anti-inflammatory drug (NSAID), wherein said patient has not previously had a TKR.

[0104] When administered to the joint, the biodegradable drug delivery composition can be subjected to a mechanical challenge via internal structures of the joints, articulation, weight bearing and / or by synovial fluid pressure. This mechanical challenge is believed to aid in the morselization of the biodegradable drug composition. In this morselization process the biodegradable drug delivery composition is broken into pieces. These pieces are taken up by the synovial tissues and can be further degraded over time into smaller and smaller pieces. These smaller pieces can range from 1 centimeter down to 1 millimeter and further down to 1 micron.

[0105] The nonsteroidal anti-inflammatory drug (NSAID) can be present in the biodegradable drug delivery composition in an amount of 1 % to 85% w% / w%, 1 % to 60% (wt% / wt%), or 10% to 60% (wt% / wt%), or 10% to 30% (wt% / wt%), or 10% to 20% (wt% / wt%), or about 15% (wt% / wt%) of the total composition. In another embodiment the NSAID can be present in the biodegradable drug composition in an amount of 1% to 40% w% / w%. In another embodiment the NSAID can be present in the biodegradable drug delivery composition in an amount of 5% to 40% w% / w%. In another embodiment the NSAID can be present in the biodegradable drug delivery composition in an amount of 5% to 15% w% / w%. In yet another embodiment the NSAID can be present in the biodegradable drug delivery composition in an amount of 5% to 30% w% / w%.

[0106] The biodegradable drug delivery composition may further include anti-oxidant agents such as alkyl gallates, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), alpha-tocopherol, ascorbic acid, polyphenols, flavonoids, beta-carotene, vitamin A, vitamin C, vitamin E, lipoic acid, dithiolethione, ovothiol, glutathione, selenium, quercetin, melatonin, sodium sulfite, sodium bisulfite, sodium metabisulfite, thiogly colic acid, monothioglycerol, L- cysteine or a combination thereof.

[0107] Possible NSAID compounds include non COX-2 or COX-2 specific such as COX-2 inhibitors, mPEGS-1 inhibitors, EP4-receptor antagonists, etofenamate, celecoxib, apricoxib, rofecoxib, nabumetone, benorilate, etoricoxib, ampiroxicam, aminophemazone, valdecoxib, acetominophen, bufexamac, nimesulide, parecoxib, mefenamic acid, dexibuprofen, ibuprofen, flurbiprofen, aspirin, dexketoprofen, diclofenac, diflunisal, etodolac, fenoprofen, firocoxib, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, loxomac, lumiracoxib, meclofenamic acid, meloxicam, naproxen, naprosyn, nimalox, oxaporozin, piroxicam, salsalate, sulindac, tenoxicam, tolfenamic acid and mixtures thereof.

[0108] The NSAID may be at least one of etofenamate, celecoxib, apricoxib, rofecoxib, nabumetone, benorilate, etoricoxib, ampiroxicam, aminophemazone, valdecoxib, acetominophen, bufexamac, nimesulide, parecoxib, mefenamic acid, dexibuprofen, ibuprofen, flurbiprofen, aspirin, dexketoprofen, diclofenac, diflunisal, etodolac, fenoprofen, firocoxib, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, loxomac, lumiracoxib, meclofenamic acid, meloxicam, naproxen, naprosyn, nimalox, oxaporozin, piroxicam, salsalate, sulindac, tenoxicam, tolfenamic acid, and ropivicaine. Preferably the NSAID is a COX-2 inhibitor, more preferably the NSAID is celecoxib. Mixtures of the NSAIDs, as described herein, can also be administered. This mixture depends on the symptoms of the patient.

[0109] The drug delivery composition may also include local anesthetics agents such as bupivacaine, mepivicaine, articaine, ropivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocalne, and the like including mixtures and / or salts and / or derivatives thereof.

[0110] In one embodiment, the composition comprises celecoxib in an amount of 13% to 17% (wt% / wt%), the triblock copolymer in an amount of 7% to 9% (wt% / wt%), the diblock copolymer in an amount of 30% to 34% (wt% / wt%), and dimethyl sulfoxide in an amount of 43% to 47% (wt% / wt%) of the total composition.

[0111] Typically, the composition is administered to said patient in a volume of 0.1 to 6 ml or 2 to 5 mL or 3 to 4 mL. Typically, the composition has concentration of celecoxib of from about 150 mg / mL to about 200 mg / mL, or from about 170 to about 190 mg / mL.

[0112] In one embodiment, about 625 mg of celecoxib is administered to the patient. In a preferred embodiment, the composition is administered to said patient in a volume of about 3.5 mL.

[0113] Typically, the maximal celecoxib plasmatic concentration reached after a single administration of a composition according to the invention comprising celecoxib is less than 200 ng / mL, optionally less than 180 ng / mL, optionally less than 160 ng / mL 24 hours after the TKR.

[0114] Typically, a therapeutically effective concentration of the NSAID is released for a period of at least 4 weeks, preferably at least 6 weeks.

[0115] In the methods of the invention, as described herein, the molecular weight of the polyethylene glycol chain in the triblock and the diblock can range from 300 Da to 12 kDa. In another aspect, the molecular weight of the polyethylene glycol chain in the triblock and the diblock can range from 5 kDa to 8 kDa. In yet another aspect the molecular weight of the polyethylene glycol chain in the triblock and the diblock can range from 1 kDa to 5 kDa. In still yet another aspect the molecular weight of the polyethylene glycol chain in the triblock and the diblock can range from 1 kDa to 2 kDa. In yet another aspect, the molecular weight of the polyethylene glycol chain in the triblock is 2 kDa and the diblock is 1 kDa. In still yet another aspect the molecular weight of the polyethylene glycol chain in the triblock is 1 kDa and the diblock is 2 kDa. In one embodiment the polyethylene glycol chain in the triblock and / or the diblock copolymer has a molecular weight of from 1 .5 to 2.5 kDa.

[0116] In still yet another aspect the molecular weight of the polyethylene glycol chain in the triblock is about 2 kDa and the diblock is about 2 kDa.

[0117] The molecular weight referred above can be the number average molecular weight (Mn) or the weight number molecular weight (Mw), typically it can be the number average molecular weight. The number average molecular weight (Mn) and the weight number molecular weight are typically measured by gel permeation chromatography (GPC), usually with a polystyrene standard. The polydispersity index is defined as the ratio of Mw over Mn and is typically above 1 and below 2.

[0118] In addition, or as an alternative to defining the polymer in terms of number average molecular weight, the polymers can be defined in terms of their theoretical molecular weight. The term “theoretical molecular weight” refers to the molecular weight of the copolymer determined by calculating the sum of the molar weights of the repeat units making the polymer. The theoretical molecular weight indicates the average length of the target polymer chains.

[0119] In the methods of the invention, as described herein, the lactic acid to ethylene oxide molar ratio for the triblock copolymer can be from 1 .6 to 7.2 or 1.6 to 5.0 or 1.6 to 3.0, or about 2.0.

[0120] In the methods of the invention, as described herein, the lactic acid to ethylene oxide molar ratio for the diblock copolymer can be from 1.6 to 7.2 or 1 .6 to 5.0 or 1.9 to 4.8, or 1 .9 to 3.0, or about 2.4.

[0121] In one embodiment, the lactic acid to ethylene oxide molar ratio is 1.6 to 7.2 in the triblock copolymer and 1.9 to 4.8 in the diblock copolymer.

[0122] In another embodiment the lactic acid to ethylene oxide molar ratio can range from 2.0 to 6.0 in the triblock and 2.0 to 3.0 in the diblock. In yet another aspect the lactic acid to ethylene oxide molar ratio can range from 3.0 to 6.5 in the triblock and 2.5 to 4.5 in the diblock copolymer.

[0123] The lactic acid to ethylene oxide molar ratio is typically determined by1H-NMR.

[0124] Degree of polymerization is the total number of repeat number units of ethylene oxide and lactic acid; i.e. v+w+x for the triblock copolymer or y+z for the diblock copolymer.

[0125] Typically, the degree of polymerization in the triblock copolymer is from 92 to 135 and the degree of polymerization in the diblock copolymer is from 91 to 180, or the degree of polymerization in the triblock copolymer is 95 to 130 and the degree of polymerization in the diblock copolymer is from 95 to 175, or the degree of polymerization in the triblock copolymer is 99 to 132 and the degree of polymerization in the diblock copolymer is from 95 to 175, or the degree of polymerization in the triblock copolymer is 100 to 170 and the degree of polymerization in the diblock copolymer is from 115 to 195. In one embodiment, the triblock copolymer is present in an amount of 2% to 45% (wt% / wt%), or 6% to 24% (wt% / wt%), or 6% to 15% (wt% / wt%), 6% to 10% (wt% / wt%), or about 8% (wt% / wt%) of the total composition.

[0126] In one embodiment, the diblock copolymer is present in an amount of 8% to 50% (wt% / wt%), or 12% to 40% (wt% / wt%), or 20% to 40% (wt% / wt%), or about 32% (wt% / wt%) of the total composition.

[0127] In one embodiment, the triblock copolymer is present in an amount of 6% to 24% (wt% / wt%) and the diblock copolymer is present in an amount of 12% to 40% (wt% / wt%) of the total composition. Typically, the total polymer content ranges from 20% to 50% (w% / w%) or 30% to 50% (w% / w%), or about 40% (w% / w%) of the total composition.

[0128] In one embodiment the triblock can be present in an amount of 5% to 30% (wt% / wt%) and the diblock can be present in an amount of 15 % to 25% (wt% / wt%) in the biodegradable drug composition. In one embodiment, the triblock can be present in an amount of 10% to 40% (wt% / wt%) and the diblock can be present in an amount of 10% to 20% (wt% / wt%) in the biodegradable drug composition. In one embodiment the triblock can be present in an amount of 15% to 50% (wt% / wt%) and the diblock can be present in an amount of 5% to 35% (wt% / wt%) in the biodegradable drug composition.

[0129] In one embodiment, the total polymer content ranges from 30% to 50% (w% / w%) of the total composition and the NSAID is present in an amount of 10% to 20% (w% / w%) of the total composition.

[0130] Preferably, the composition further comprises a pharmaceutically acceptable vehicle. Typically, the pharmaceutically acceptable vehicle is a biocompatible organic solvent. The biocompatible organic solvent may be selected from the group of: benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl- 2-pyrrolidone, N-methyl-2-pyrrolidinone (NMP), pyrrolidone-2, tetraglycol, triacetin, tributyrin, tripropionin (tripro) and mixtures thereof. In one embodiment the solvents are DMSO, tripo, NMP and mixtures thereof, preferably DMSO.

[0131] In the methods of the invention, as described herein, the formulation of said biodegradable drug composition comprises mixing the triblock copolymer with the diblock copolymer in a biocompatible organic solvent to form a triblock copolymer and diblock copolymer mixture. The NSAID is then added to said triblock copolymer and diblock copolymer mixture. The solvent can be evaporated off.

[0132] The type of TKR carried out is not especially limited. For example, any known total knee replacement implant, partial knee replacement implant, or knee replacement surgical method can be used. The surgery is typically carried out under general or spinal anaesthesia. Intravenous sedatives are typically administered perioperatively, for example propofol or midazolam.

[0133] The biodegradable drug delivery composition is typically administered via a syringe into the intra-articular space at the end of TKR surgery, just prior to wound closing. Typically, just prior to administration, joint fluid is aspirated to the greatest extent possible. The composition of the invention is typically administered to the lateral gutter of the knee at the level of the lateral femoral condyle. The formulation is administered only after any knee flexion during, for example implant fitting or alignment testing, and just prior to closing, to prevent unwanted discharge and loss of the composition of the invention through the arthrotomy.

[0134] Typically, the methods of the invention further comprise the administration of standardized multimodal analgesia (MMA).

[0135] The limitations of opioid-based analgesia and increased understanding of pain physiology have led the way to alternative pain management approaches, collectively known as multimodal analgesia. First introduced by Kehlet and Dahl in 1993, the primary goal of multimodal analgesia is to decrease the reliance on opioids and therefore minimize opioid- related side effects. Multimodal analgesia is a combination of more than one pharmacological class of analgesic medication targeting different receptors along the pain pathway with the goal of improving analgesia while reducing individual class-related side effects.

[0136] Multimodal analgesia (MMA) is the current standard of care for post-TKR pain management and involves a selection of analgesics that target different, but complementary, sites of action. Generally, this can include opioids, acetaminophen, periarticular injections, peripheral nerve blocks, pregabalin for neuropathic pain and anti-inflammatory drugs.

[0137] Evidence today supports the routine use of multimodal analgesia in the perioperative period to eliminate the over-reliance on opioids for pain control and to reduce opioid-related adverse events. The specific combination of medications and doses thereof making up the multimodal analgesia will depend on the surgeon’s experience and patient medical history.

[0138] The methods of the invention typically involve concurrent administration of the standardized multimodal analgesia. The timing of administration of each medication making up the multimodal analgesia will depend on the specific medication and the purpose thereof, as well as the needs of the particular patient. Thus, the standardized multimodal analgesia may be administered, prior to, during and / or after TKR. The methods of the invention provide an improvement in treatment or management of pain or inflammation relative to the administration of the standardized multimodal analgesia alone.

[0139] The standardized multimodal analgesia may comprise two or more active pharmaceutical ingredients selected from bupivacaine, ropivacaine, lidocaine, acetaminophen, methocarbamol, pregabalin, gabapentin, ketamine, morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, tramadol, tapentadol, a nerve block and dexamethasone. In one embodiment, the standardized multimodal analgesia comprises bupivacaine hydrochloride, acetaminophen and methocarbamol.

[0140] It will be noted that methocarbomol is a muscle relaxant used for the treatment of back or leg muscles, thus it is not strictly an analgesic for the knee. Thus in some embodiments, methocarbamol is not included in the above list of multimodal analgesics and may be administered in addition to the standardized multimodal analgesia.

[0141] A nerve block may be administered by injection or indwelling catheter. The nerve block may be administered to the femoral nerve or adductor canal.

[0142] Gabapentinoids such as pregabalin or gabapentin can be administered to treat neuropathic pain.

[0143] Bupivacaine, ropivacaine, or lidocaine can be administered via periarticular infiltration, typically via injection into soft tissues in the knee.

[0144] Opioids, such as morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, tramadol, tapentadol or combination thereof, can be orally or intravenously administered to treat severe pain. In addition to the NSAID administered in the biodegradable drug delivery composition, in one embodiment, one or more further NSAIDs may be administered separately as part of the multimodal analgesia. The one or more further NSAIDS may be selected from celecoxib, meloxicam, diclofenac, ibuprofen, naproxen or combinations thereof.

[0145] In one embodiment, bupivacaine is administered via periarticular infiltration using a mixture of 0.25% bupivacaine with epinephrine (1 :200,000) and 0.25% bupivacaine without epinephrine at a ratio of 2:1 respectively for subjects weighing less than 80 kg, and at a ratio of 3:1 respectively for subjects weighing more than 80 kg at 1 mL / kg up to 90 mL. The bupivacaine is typically administered during the intra-operative period. Bupivacaine is a local anaesthetic. Post TKR, oral acetaminophen is administered, and methocarbamol when needed. Acetaminophen is an analgesic and methocarbamol is a muscle relaxant. Acetominophen is administered orally, typically 650 mg every 8 hours (up to 1950 mg / day) for up to 6 weeks post TKR. Methocarbamol is typically administered at a dose of 750 mg every 8 hours.

[0146] The standardized multimodal analgesia typically comprises an opioid. The opioid may be administered orally or intravenously. The opioid may be selected from but not limited to morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, tramadol, tapentadol and combinations thereof. In one embodiment the opioid is morphine and / or oxycodone. Each opioid dosing regimen will be prescribed depending on surgeon, patient need and tolerance (such as, for example, oral 10 mg immediate-release oxycodone every 4-hour period to a maximum of 60 mg / day). An advantage of the present invention is that opioid consumption is reduced, reducing the risk of opioid addiction.

[0147] In one embodiment mean cumulative opioid consumption of the patient is reduced relative to a patient receiving only the standardized multimodal analgesia comprising opioid, optionally wherein opioid consumption is reduced from 2 weeks to 90 days after the TKR, or over 2 weeks, or 4 weeks, or 6 weeks, or 8 weeks or 12 weeks, or 90 days after the TKR.

[0148] In one embodiment, when analyzing all patients, there is from a 15% to 20% reduction in cumulative opioid consumption 90 days after the TKR. In one embodiment, for patients who have had no previous TKR, there is from a 25% to 30% reduction in cumulative opioid consumption 90 days after the TKR.

[0149] In one embodiment the daily opioid consumption of the patient is reduced relative to a patient receiving only the standardized multimodal analgesia comprising opioid, optionally wherein the daily opioid consumption is reduced from 2 weeks to 90 days after the TKR, or over 2 weeks, or 4 weeks or 6 weeks, or 12 weeks or 90 days after the TKR.

[0150] Typically, the daily opioid consumption or mean cumulative opioid consumption is measured in Morphine Milligram Equivalents (MME).

[0151] Daily opioid consumption in oral Morphine Milligram Equivalents (MME) is determined by tallying the total daily dose of the opioid (Dose taken x Frequency per day), and using a conversion factor to convert to the equivalent amount of oral morphine sulfate, referred to as the morphine equivalent daily dose (MED).

[0152] Cumulative opioid consumption in MME over a time period in Morphine Milligram Equivalents (MME) is determined by tallying the total daily dose of the opioid (Dose taken x Frequency per day), and using a conversion factor to convert to the equivalent amount of oral morphine sulfate, referred to as the morphine equivalent daily dose (MED), followed by cumulative summation over the time period, e.g. 90 days.

[0153] In one embodiment there is a reduction in Area Under the Curve (AUC) of Numeric Rating Score (NRS) pain of the patient at 3 days, 7 days, 2 weeks, 6 weeks or 90 days after the TKR relative to a patient receiving only the standardized multimodal analgesia. Optionally, the reduction is calculated based on the least squares mean of AUC of NRS. In one embodiment, the reduction in least squares mean of AUC of NRS pain of the patient relative to a patient receiving only the standardized multimodal analgesia may be at least 3%, optionally least 4%, optionally at least 5%, optionally at least 6%. In patients with no previous TKR, the reduction in least squares mean of AUC of NRS pain of the patient relative to a patient receiving only the standardized multimodal analgesia may be at least 8%, optionally at least 9%, optionally at least 10%, optionally at least 12%, optionally at least 14%, optionally at least 16%.

[0154] In one embodiment the AUC of Numeric Rating Score (NRS) pain is statistically adjusted or imputed for consumption of opioids. Statistical adjustment is carried out using the windowed worst observation carried forward (wWOCF) imputation (N. K. Singla et al, Pain Ther. 2017 Dec; 6(2): 165-175, “Exploring the Interplay between Rescue Drugs, Data Imputation, and Study Outcomes: Conceptual Review and Qualitative Analysis of an Acute Pain Data Set”). This method is used to prevent NRS pain scores recorded by a patient from being artificially low due to the therapeutic action of an opioid. In this method, NRS scores collected during the therapeutic window of a consumed opioid (e.g., 4 hours for oxycodone) are replaced with the NRS score collected immediately prior to opioid consumption.

[0155] Post-operative pain intensity is recorded using a numeric rating score or scale (N RS- 11). The NRS consists of a segmented numerical scale with 11 points ranging from 0 to 10, with 0 being no pain and 10 being the worst imaginable pain. Patients are asked to select a corresponding number to indicate the pain intensity they are experiencing. This scale can be administered verbally or graphically. The AUG of Numeric Rating Score is the time weighted area under the curve for the NRS.

[0156] Pain can also be assessed using a continuous visual analog scale (VAS) comprised of a 10-cm horizontal line, anchored by 2 verbal descriptors, “no pain” (score of 0) and “pain as bad as it could be” or “worst imaginable pain” (score of 10). Patients are asked to report maximum pain intensity “in the last 24 hours.” The VAS scale is displayed as a 10-cm line and is measured with a ruler. The least squares mean of the VAS value can be determined.

[0157] In another embodiment, there is a reduction in the least squares mean of the Visual Analog Scale (VAS) for pain of the patient at 2 weeks, 6 weeks or 90 days after the TKR relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the reduction is at least an 10%, optionally at least a 20% difference in least squares mean of the VAS.

[0158] In one embodiment the patient has a reduced time period to a knee range of motion of between 100 and 110 degrees relative to a patient receiving only the standardized multimodal analgesia.

[0159] In another embodiment the patient has an improved knee range of motion (ROM) relative to a patient receiving only the standardized multimodal analgesia between 1 week and 3 months after the TKR or at 1 week, or at 2 weeks, or at 3 weeks, or at 6 weeks, or at 12 weeks after the TKR, optionally wherein there is a 5 to 10% improvement of ROM relative to a patient receiving only the standardized multimodal analgesia at 3 months after the TKR.

[0160] The passive ROM of the index knee in flexion and extension is measured by goniometer with the subject in the supine position to prevent interference from rectus femoris muscle tightness. The fixed arm of the goniometer is placed in between the greater trochanter of the femur and the middle portion of the femur, and the moving arm positioned in a straight line from the fibular head to the lateral malleolus of the ankle. To reduce measurement errors, the mean value from three repeated measurements should be recorded.

[0161] In one embodiment there is a reduction in effusion of the knee of the patient measured as the percentage difference in circumference of the knee which has had a TKR relative to the contralateral knee and relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the measurement is made at 2 weeks, or at 6 weeks or at 3 months after the TKR.

[0162] A tape measurement method is used to measure effusion of the index knee as a marker of inflammation. The measurement method uses a standardized, sterile, disposable soft tape measure to measure the circumference at a location 5 cm above the knee joint line, while the subject is in a supine position. Both the index and the contralateral knees should be measured. To reduce measurement errors, the mean value from three repeated measurements is required.

[0163] In a further embodiment there is an improvement in mobility of the patient as measured by the Timed Up and Go Test relative to a patient receiving only the standardized multimodal analgesia, wherein the Timed Up and Go Test measures the time it takes for the patient to stand up, walk a distance of 3 meters (10 feet), turn, walk back and sit down again, optionally wherein the Timed Up and Go Test result is measured at 2 weeks or 6 weeks or 3 months after the TKR.

[0164] The Timed Up and Go test (TUG) is a simple, validated test (T.S. Yeung, J. Wessel, P.W. Stratford, J.C. MacDermid, The timed up and go test for use on an inpatient orthopaedic rehabilitation ward, The Journal of orthopaedic and sports physical therapy 38(7) (2008) 410- 7.), used to assess a person's functional mobility after orthopedic surgery. It uses the time that a person takes to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down. During the test, the person is expected to wear their regular footwear and use any mobility aids that they would normally require. Time taken to complete the test is recorded to the nearest 1 / 100 of a second using a stopwatch.

[0165] In one embodiment, the physical functioning and / or the composite score of the Physical Component Summary score of the Short Form 12 (SF-12v2) Health Survey is increased by at least 15% or at least 30% from the value for a patient receiving only the standardized multimodal analgesia. The Short Form 12 (SF-12v2) Health Survey is a survey which assesses the functional status and well-being of the subject using 12 questions covering selected concepts including physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role- emotional, and mental health. The SF-12v2 data is used to calculate the subject’s utility values. Outcomes can be summarized using the Physical Component Summary (PCS) score and the Mental Component Summary (MCS) score.

[0166] In an additional embodiment the health status of a patient as measured by the EuroQoL 5D (EQ-5D-5L) index 2 weeks after the TKR is improved relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the index increases by at least 70, or at least 85 from the value for a patient receiving only the standardized multimodal analgesia. In an embodiment of the invention where patients have not had a previous TKR, the index 2 weeks after the TKR may increase by at least 150, or at least 170 from the value for a patient receiving only the standardized multimodal analgesia.

[0167] The EuroQoL 5D (EQ-5D-5L) is a standardized measure of health status of the subject utilizing 5 questions and a VAS scale covering selected dimensions. The dimensions cover mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. The responses for each dimension record five levels of severity (no problems, slight problems, moderate problems, severe problems and extreme problems). The utility value is based on an individual’s response to the 5 questions. The higher utility value indicates better health status.

[0168] In one embodiment, the Knee Society Score 2011 (KSS2011) of a patient as measured 2 weeks after the TKR is improved relative to a patient receiving only the standardized multimodal analgesia, optionally wherein there is at least a 30%, or at least a 40%, or at least a 50% increase in the KSS2011 patient satisfaction and / or functional activities score of a patient relative to a patient receiving only the standardized multimodal analgesia. For patients who have not previously had a TKR, there is there is typically at least a 40%, or at least a 50%, or at least a 60% increase in the KSS2011 patient satisfaction and / or functional activities score of a patient relative to a patient receiving only the standardized multimodal analgesia.

[0169] The Knee Society Knee Scoring System (KSS), updated in 2011 , is a validated system that combines an objective physician-derived component with a subjective patient-derived component that evaluates pain relief, functional abilities, satisfaction, and fulfillment of expectations. This score prioritizes the patient perspective, to track patient expectations, satisfaction, and activity levels. In one embodiment said biodegradable drug delivery composition is taken up by syringe for administration and injected into said knee joint or manually formed in into a solid bolus by exposing the formulation to aqueous liquid and manual placement into the knee joint.

[0170] In one embodiment said biodegradable drug delivery composition is subjected to a mechanical challenge. Typically, said mechanical challenge is obtained by internal structures of the joints, articulation, weight bearing and / or by synovial fluid pressure.

[0171] In a further aspect, the invention provides a composition for use in a method as defined above.

[0172] To those skilled in the art, other drugs or biologically active agents that can be released in an aqueous environment can be utilized in the described delivery system. Also, various forms of the drugs or biologically active agents may be used. These include without limitation forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, etc., which are biologically activated when injected into the animal or used as a spatial formulation such that it can be applied on or inside the body of an animal or as a rod implant.

[0173] The pharmaceutically effective amount of the NSAID or other active principle may vary depending on the NSAID or other active principle, the extent of the animal’s pain and the time required to deliver the active principle. There is no critical upper limit on the amount of active principle incorporated into the polymer solution except for that of an acceptable solution or dispersion viscosity for injection through a syringe needle and that it can effectively manage pain without subjecting the human or animal patient to an overdose. The lower limit of the active principle incorporated into the delivery system is dependent simply upon the activity of the active principle and the length of time needed for treatment.

[0174] Typically, for the treatment of humans, the NSAID is present in the composition at a concentration of from about 150 mg / mL to about 200 mg / mL, optionally about 160 mg / mL to about 190 mg / mL, optionally about 170 mg / mL to about 190 mg / mL.

[0175] In the biodegradable drug delivery composition used with the present invention, the pharmaceutically effective amount of the NSAID can be released gradually over an extended period of time. This slow release can be continuous or discontinuous, linear or non-linear and can vary due to the composition of the triblock copolymer and diblock copolymer. Thus, the higher the lactic acid content of the triblock and diblock copolymers in comparison with the polyethylene glycol content, as well as the amount of triblock and diblock copolymers present in the biodegradable drug composition the longer the release of the active principle or drug. In other words, the higher the LA / EO molar ratio and the greater weight percentage of the triblock and diblock copolymers, the longer it will take for the active principle to be released from the drug composition.

[0176] The biodegradable drug delivery composition can be an injectable liquid at room temperature and be injected through a syringe without excessive force. But these biodegradable drug delivery compositions are also in situ forming and biodegradable and turn into solid implants or depots when put in contact with aqueous liquids after injection into a human or animal patient. Alternatively the biodegradable drug composition is produced as a solid, prepared as small particles and used as a powder which is sprinkled on the injured site. In another aspect the drug delivery composition is a rod implant, which can be implanted under the skin or in another compartment in the body. In another aspect the drug delivery composition can be prepared and applied as a film. In yet another aspect the biodegradable delivery drug composition can be used as a spatial formulation such that it can be applied onto or inside the body of a human or animal patient.

[0177] Some mPEG-OH are contaminated with a small amount of OH-PEG-OH. By following the methods of the present invention and using the contaminated mPEG-OH the final product would be mPEG-PLA contaminated with a small amount of PLA-PEG-PLA, which is encompassed by the present invention.

[0178] A number of embodiments and / or aspects of the invention have been described. Nevertheless it will be understood that various modifications may be made without departing from the spirit and scope of the invention.

[0179] EXAMPLES

[0180] Example 1- Polymer synthesis

[0181] Copolymers were synthesized according to the method described in U.S. Patent No. 6,350,812, incorporated herein by reference, with minor modifications. Typically, the necessary amount of PEG (gives the triblock co-polymer) or methoxy-PEG (gives the diblock copolymer) was heated at 65°C and dried under vacuum for 2 hours in a reactor vessel. D,L-lactide (corresponding to the targeted lactic acid / ethylene oxide (LA / EO) molar ratio) and zinc lactate (1 / 1000 of amount of lactide) were added. The reaction mixture was first dehydrated by three short vacuum / N2 cycles. The reaction mixture was heated at 140°C and rapidly degassed under vacuum. The reaction was conducted for four days at 140°C under constant nitrogen flow (0.2 bar). The reaction was cooled to room temperature and its content was dissolved in acetone and then subjected to precipitation with ethanol. The product obtained was subsequently dried under reduced pressure. Alternatively, the copolymers may be purchased from Corbion.

[0182] The product obtained was characterized by 1 H NMR for its residual lactide content and for the determination of the LA / EO molar ratio. 1 H NMR spectroscopy was performed using a Brucker Advance 300 MHz spectrometer. For all 1 H NMR spectrograms, TopSpin software was used for the integration of PLA and PEG characteristic peaks and their analyses. Chemical shifts were referenced to the 6 = 7.26 ppm solvent value of CDCI3.

[0183] The product obtained was further characterized by gel permeation chromatography (GPC) for the determination of its molecular weight distribution. GPC was performed using a LC system equipped with a refractive index detector. The equipment can be equipped with a series of Waters styragel columns selected from HR4, HR3 HR2 and HR1 kept at constant temperature. The sample are run in BHT-stabilized THF at a constant flow rate. Molecular weights distributions (Mn; Mw and polydispersity index) are determined by conventional calibration using polystyrene calibration standards.

[0184] The triblock polymers described herein were labelled PxRy where x represents the size of the PEG chain in kDa and y is the LA / EO molar ratio. The diblock mPEG-PLA polymers described herein where labelled dPxRy where x represents the size of the PEG chain in kDa and y is the LA / EO molar ratio.

[0185] Example 2- Formulation Preparation Specific for Celecoxib

[0186] The formulations described herein were based on organic solution of polymers containing as the drug, celecoxib. Typically, 0.4 grams of polymers, corresponding to a mix of a diblock copolymer and a triblock copolymer in defined mass ratio, were dissolved in 0.57 grams of a biocompatible solvent at room temperature overnight under constant magnetic stirring. The solvent was either a single solvent or a combination of solvents. The next day, 20 mg of celecoxib was added to the polymer solution and stirred until complete dissolution. When the drug was not soluble in the solvent, a suspension of the drug in a polymer solution was obtained. Alternatively, the drug was dissolved or suspended in the biocompatible solvent and the polymer(s) added subsequently. The final formulation F14 is set out in Table 1 below. The formulations were loaded into a syringe before use.

[0187] Table 1 : Composition of formulation F14

[0188] *The PLA used in the polymers of formulation F14 is poly-D,L-Lactide.

[0189] Example 3

[0190] A Phase 2, randomized, single-blind, active-control, parallel group study was carried out to evaluate the safety and activity of a single administration of formulation F14 for management of postoperative pain in patients undergoing unilateral total knee replacement.

[0191] Nine patients were administered a single, 3.5 mL dose (625 mg celecoxib) of F14 concurrent with a protocol-defined multimodal analgesia (MMA) and were compared to 11 subjects who received MMA alone. Randomization was stratified by whether or not a patient had received a previous, contralateral TKR. The F14 formulation was administered via a syringe into the joint space intra-operatively, at the end of surgery and just prior to wound closing. Safety was evaluated through recording of adverse events, vital signs, ECG, physical and knee-specific examinations, laboratory blood tests and standing x-rays of the TKR obtained at 3 and 12 months. Post-operative pain was assessed using visual analog scores (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (Part A) questionnaires, and stiffness and function will be assessed by WOMAC (Part B, C) questionnaires and the Timed Up and Go test. Concomitant medication usage and rescue medication including morphine milligram equivalents, was recorded at the hospital and then monitored daily for 3 months with patient drug diaries, and at the 12-month visit. Perceived benefit of analgesia was compared using the Overall Benefit of Analgesic Score (OBAS). The pharmacokinetic profile of celecoxib in plasma was assessed up to 3 months and at 12 months. Patients were screened within 30 days before TKR surgery. Patients were only randomized to study intervention upon successful TKR surgery in the opinion of the Investigator. The participants remained in the hospital for at least 24 hours following TKR (or longer if indicated). Standardized physical therapy was implemented post-operatively. Follow-up study visits occurred at 1 , 2, 3, 4 (phone) and 6 weeks, 3 and 12 months.

[0192] Objectives

[0193] The study primary objective was to assess the safety of a single intra-operative administration of F14 concurrent with standard of care analgesia in participants undergoing unilateral total knee replacement.

[0194] Secondary objectives were to investigate the efficacy of a single intra-operative administration of F14 concurrent with standard of care analgesia to improve postoperative pain and function in participants undergoing unilateral total knee replacement, when compared to standard of care alone.

[0195] Other objectives of this study were to investigate opioid-sparing effects and overall analgesic benefit of a single intra-operative administration of F14 concurrent with standard of care analgesia in participants undergoing unilateral total knee replacement, when compared to standard of care alone.

[0196] In addition, the study determined the pharmacokinetic profile of celecoxib in plasma following a single intra-operative administration of F14 in participants undergoing unilateral total knee replacement. Concomitant Medication

[0197] Pain management in the Post Anesthesia Care Unit (PACU) was limited to fentanyl, if needed.

[0198] During each participants’ post-operative hospital stay until discharge, all participants were administered:

[0199] • Oral acetaminophen - 1000 mg every 8 hours

[0200] • Methocarbamol (muscle relaxants) - 750 mg every 8 hours p.r.n.

[0201] • Non-aspirin DVT prophylaxis (e.g. Fondaparinux, Rivaroxaban, Apixaban, Enoxaparin)

[0202] In addition, according to participant tolerance and need, the following narcotics could be administered according to need:

[0203] • Oral oxycodone - 5-10 mg p.r.n. every 4 hours

[0204] • Morphine ER - 15 mg p.r.n. every 12 hours (for participants under 70 years old)

[0205] • For break-through pain: IV hydromorphone - 0.2 mg / mL

[0206] For less opioid-tolerant participants:

[0207] • Oral hydromorphone - 2-4 mg p.r.n. every 4 hours

[0208] • Oral hydrocodone - 5 / 325 mg (1-2 tabs) p.r.n. every 4 hours Tapentadol - 50-100 mg p.r.n. every 4 hours

[0209] Tramadol - 50-100 mg p.r.n. every 4 hours

[0210] Drug dosage and frequency of administration was adjusted, as needed.

[0211] Following discharge, participants under 70 years old were prescribed pregabalin (75 mg b.i.d). Participants could take acetaminophen for pain up to 3000 mg / day in addition to rescue medication as described above. No anti-inflammatory medications were permitted (including low-dose aspirin as cardiac prophylaxis and cannabidiols) other than meloxicam until 3 months’ post-intervention.

[0212] The date and time of all medications taken by the participant after discharge was recorded daily by each participant in their drug diary up to the 3-month visit.

[0213] Opioids

[0214] Opioids were prescribed to participants at discharge according to in-hospital tolerance:

[0215] • Oral oxycodone - 5-10 mg p.r.n. every 4 hours.

[0216] • Morphine ER - 15 mg b.i.d (for participants under 70 years old)

[0217] For less-tolerant participants:

[0218] • Oral hydromorphone - 2-4 mg p.r.n. every 4 hours

[0219] • Oral hydrocodone - 5 / 325 mg 1-2 tabs p.r.n. every 4 hours

[0220] • Tapentadol - 50-100 mg p.r.n. every 4 hours

[0221] • Tramadol - 50-100 mg p.r.n. every 4 hours

[0222] If and only if, narcotics were insufficient to manage a patients post-operative pain, they may request a prescription for the NSAID:

[0223] Meloxicam - 7.5 mg b.i.d or 15mg once a day.

[0224] The date and time of opioid medication taken by the patient were recorded daily by each participant in their drug diary for 3 months. In addition, total medication use was determined as the total number of pills of each type prescribed to the patient at discharge and during the follow-up period minus the remaining number of pills at the time of each follow-up appointment.

[0225] Patients who took opioid medication during the study were followed through the end of study for safety and efficacy.

[0226] Results This Phase 2 study found that F14 administered concurrently with MMA was well tolerated. The safety profile of the MMA+F14 group was comparable to the MMA alone control group. Despite the small study size, F14 showed clinically meaningful efficacy for postsurgical pain in lowering VAS Pain scores when compared to MMA over both 2 week and 3 month postoperative periods (see Figure 2). Compared to VAS scores at 24hrs post-operative, a greater than 50% decrease in VAS scores was observed in 9 days for subjects administered F14+MMA versus 4 weeks in subjects administered MMA alone (controls).

[0227] Associated functional improvement was also observed for the MMA+F14 group at 1 and 2 weeks. Side-by-side analysis showed a clear opioid sparing effect was seen with F14+MMA over MMA alone, in the absence of other factors impacting subject consumption. In this study efficacy was supported by consistent and concordant trends observed from multiple manifestations of postoperative pain and related endpoints. Concordant trends in multiple manifestations of efficacy are unlikely to be observed by chance alone even when sample size is limited.

[0228] The most noteworthy efficacy findings after F14 treatment compared to MMA alone were: up to 47.2% lower daily knee pain scores over 90-days post-operative, characterized by a more rapid and consistent decline in VAS scores (Figure 2) improved knee range-of-motion at every time-point over the 12-month follow-up (see Figure 3 plotting the knee range range-of-motion in degrees versus time for the first 6 weeks) a more rapid improvement in function by the Timed-Up-and-Go test in F14 subjects. In particular, at 1 week, subjects in the F14 group completed the test an average of 34.3% faster than control subjects sustained release of celecoxib for at least 6 weeks, demonstrated by pharmacokinetic analysis as shown in Figure 1

[0229] Figure 1 shows the plasma concentration of celecoxib over time. The maximum plasma celecoxib concentration was 155.3 ng / mL at 24 hours post-TKR. Due to the acute dosing regimen and local route of administration, it is understood that the systemic adverse events associated with oral celecoxib will be largely avoided with methods of the invention. The maximum plasma celecoxib concentration (155.3 ng / mL) at 24 hours post-TKR in the Phase 2 study represents only 15% of that (1042 ng / mL) following the general dosing recommendations for oral celecoxib (ranging from 200-400 mg daily, chronic doses).

[0230] A single 400 mg oral dose of celecoxib produced a Cmax of 1433 ng / mL, almost exactly double the 705 ng / mL for 200 mg for Celebrex®. Since the administration of a single dose of F14 corresponded to 625mg of celecoxib, but only results in a Cmax of 155.3 ng / mL, this demonstrates the minimal systemic load compared to marketed oral versions. The systemic PK profile for celecoxib showed a very low exposure as late as 6 weeks post treatment, providing strong evidence of an intra-articular sustained drug delivery mechanism when compared to the known PK of orally delivered celecoxib.

[0231] TKR Status sub-groups were analyzed in Phase 2 with 7 / 20 (35%) subjects with previous TKR (the remainder of subjects having no previous TKR) but no statistical impact was found on efficacy due to small sample size.

[0232] Example 4 - Pain management following TKR

[0233] Phase 3 Trial

[0234] 151 subjects who met the eligibility criteria were randomized (1 :1) into two treatment groups, either protocol-defined multimodal analgesia (MMA) alone, or MMA concurrent with a single dose of F14. Of these, 108 had no history of a prior TKR with 51 receiving F14 and 57 receiving MMA. All subjects had a primary unilateral, cemented TKR under hyperbaric bupivacaine spinal anesthesia. Following installation of the TKR, all subjects received identical multimodal analgesia (MMA) defined as:

[0235] Intra-operative period:

[0236] • periarticular infiltration of 1 mL / kg (up to 90 mL) using a mixture of 0.25% bupivacaine with epinephrine (1 :200,000) and 0.25% bupivacaine without epinephrine at a ratio of 2:1 respectively for subjects weighing less than 80 kg, and at a ratio of 3:1 respectively for subjects weighing more than 80 kg.

[0237] Post-operative, in-hospital’.

[0238] • Oral acetaminophen - 650 mg every 8 hours (up to 1950 mg / day)

[0239] • Methocarbamol (muscle relaxants) - 750 mg every 8 hours p.r.n.

[0240] • Opioid rescue medication

[0241] Post-operative, post-discharge:

[0242] • Oral acetaminophen - 650 mg every 8 hours (up to 1950 mg / day) for 6 weeks

[0243] • Opioid rescue medication

[0244] In addition to the MMA described above, the F14 group of 76 subjects were administered a single, 3.5mL dose (625 mg celecoxib) of F14 via a syringe into the intra-articular (IA) space at the end of TKR surgery, just prior to wound closing.

[0245] Upon discharge, subjects received a 14-day supply of acetaminophen and opioid rescue medication. Assessments

[0246] Post-operative pain intensity was recorded using a numeric rating score (NRS-11). Pain intensity was defined as:

[0247] • Current Pain: the pain intensity that is currently being experienced

[0248] • Recall Pain: the maximum pain intensity experienced during the previous 12-hour interval

[0249] Except for at Screening and on Day 0, post-operative pain was recorded in a digital diary for 90 days at these specified times:

[0250] • Post-operatively on Day 0, Current pain was recorded on source documents, as applicable, at scheduled times of 8 am, 2 pm, 8 pm, and on Day 1 , 2 am (if awake). Current pain was also recorded on source documents immediately prior to taking any opioid rescue medication during this period.

[0251] • Starting at 8 am on Day 1 and until discharge (at 72 hours post-operative, or at least 3 pm on Day 3, whichever is later), subjects recorded both Current and Recall pain in the digital diary at scheduled times of 8 am and 8 pm, and Current pain at 2 am (if awake) and 2 pm. Current pain was also recorded in the digital diary immediately prior to taking any opioid rescue medication during this period.

[0252] • Following discharge and through 14 days, at 8 am and 8 pm, subjects recorded both Current and Recall pain in the digital diary, and Current pain at 2 pm. Current pain must was recorded immediately prior to taking any opioid rescue medication during this period.

[0253] • From 15 to 90 days, Current pain and Recall pain was recorded in the digital diary at 8 am and 8 pm. Current pain was also recorded immediately prior to taking any opioid rescue medication during this period.

[0254] Non-routine concomitant and rescue medications was recorded on source documents until 8 am on Day 1 , after which the subject entered all medications (including rescue) in the digital diary for 90 days.

[0255] Compliance to self-managed physical therapy and the need for walking aids was recorded in the digital diary at 8 am for 90 days.

[0256] Follow-up study visits occurred at 2 and 6 weeks, and 3, 6 (phone), 9 (phone) and 12 months post-operative. At 72 hours, 2 and 6 weeks, and 3 and 12 months, index knee effusion, skin temperature, and blood biomarkers (also at 24 and 48 hours, but not at 12 months) was measured to assess inflammation and range of motion (ROM) will evaluate knee function. The Timed Up and Go test was conducted at 2 and 6 weeks, and 3 months. The Knee Society Knee Scoring system (KSS2011), the Short-Form Health Survey (SF-12v2) and the EuroQoL (EQ-5D) was administered at every visit starting at 2 weeks, and working status collected.

[0257] Pain Assessment

[0258] Table 2 shows the time-weighted AUG NRS pain score versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) and patients administered MMA alone for all patients or only those patients who have not previously had a TKR.

[0259] Fig. 4 shows the percentage difference in LS mean of AUG NRS pain score for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) and patients administered MMA alone for those patients who have not previously had a TKR, statistically adjusted for consumption of opioids.

[0260] Table 2: Time-weighted AUC of Current NRS Pain with adjustment for opioid medication

[0261] Time-point F14+MMA MMA Alone

[0262] N LS N LS % LS Mean

[0263] Mean Mean Difference

[0264] ALL

[0265] AUC

[0266] 3 days 76 6.5 75 6.9 -5.8

[0267] 7 days 76 5.9 75 6.2 -4.9

[0268] 2 weeks 76 5.5 75 5.7 -3.6

[0269] 6 weeks 76 4.5 75 4.8 -4.4

[0270] 3 months 76 3.6 75 3.8 -2.7

[0271] NO TKR

[0272] AUC

[0273] 3 days 51 6.3 57 7.0 -11.4

[0274] 7 days 51 5.6 57 6.3 -11.3

[0275] 2 weeks 51 5.1 57 5.8 -10.7

[0276] 6 weeks 51 4.1 57 4.7 -10.9

[0277] 3 months 51 3.2 57 3.8 -11.1

[0278] It can be seen that in all patients, there was a consistently lower numerical difference in pain in patients receiving the F14 formulation in combination with MMA versus MMA alone at all timepoints from 3 days to 3 months after TKR. However, in the subgroup of No TKR patients, there was an enhanced treatment effect and substantial reductions in pain (at least a 10% difference in AUC NRS pain), with a statistically significant difference at 3 days, and nearing significance at 7 days and 2 weeks.

[0279] A similar magnitude in difference of 10% in AUC NRS was demonstrated in clinical studies which led to the approval of the commercial product Zynrelef (Heron), a post-TKR analgesic, based on the generally accepted minimal clinically important difference (MCID) clinical difference in pain of 10-20% (RH Dworkin, et al, “Interpreting the Clinical Importance of Treatment Outcomes in Chronic Pain Clinical Trials: IMMPACT Recommendations, The Journal of Pain, Volume 9, Issue 2, 2008, Pages 105-121).

[0280] Opioid Consumption

[0281] Fig. 5 is a graph showing mean cumulative opioid consumption in Morphine Milligram Equivalents (MME) versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (black circles) and patients administered MMA alone (white circles) for all patients (top panel) and for patients with no previous TKR (bottom panel). A clear difference in daily need for analgesia becomes evident at 2 weeks post TKR, with a final difference between the mean cumulative opioid consumption of patients receiving the F14 formulation in combination with MMA versus patients administered MMA alone of approximately 6.4% for all patients, and 13.8% for patients with no previous TKR.

[0282] Patients receiving the F14 formulation in combination with MMA consumed fewer opioids over 3 months and decreased use faster than patients receiving MMA alone.

[0283] Table 3 shows that fewer subjects in the F14+MMA group were using opioid rescue medication at 3 months after surgery than MMA Alone subjects (5.6% vs 15.9% respectively; p=0.0536), almost reaching significance for all patients, and for patients with no previous TKR (4.1% vs 13.5% respectively; p=0.1212).

[0284] Table 3: Proportion of patients using opioid medication at 3 months Knee Range of Motion

[0285] Fig. 6A is a graph showing the knee range of motion (ROM) in degrees versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (black circles) and patients administered MMA alone (white circles) for all patients (top panel) or only those patients who have not previously had a TKR (bottom panel).

[0286] Fig. 6B is an expanded version of the bottom panel of Fig. 6A showing the ROM for patients who have not previously had a TKR over the time period of 2 to 12 weeks. The critical benchmark ROM required for rehabilitation (100°) is shown with a dashed line, a benchmark for rehabilitation after TKR.

[0287] Range of motion represents a direct measurement of knee function, and a ROM of greater than 100° is positively correlated with patient satisfaction. The patient is able to ride a stationary bike and restore activities of daily life, for example walking up stairs, sitting, putting on socks, or lifting an object. A ROM of less than 100° leads to patient dissatisfaction, slows rehabilitation and restricts activities of daily living.

[0288] Fig. 6C provides a schematic for how the ROM is measured.

[0289] Table 4A below provides values for knee range of motion in degrees for all patients, and for the subgroup of patients with no previous TKR.

[0290] Table 4A: Range of Motion

[0291] There is an improvement of knee range of motion at all time points post-surgery for patients receiving the F14 formulation in combination with MMA versus MMA alone, which was highly significant and clinically relevant at 6 weeks, 3 months and 12 months. Table 4B shows the percentage of patients that achieve an ROM of 100° or greater at 6 weeks post TKR, and demonstrates a statistically significantly higher proportion for patients receiving the F14 formulation in combination with MMA versus MMA alone.

[0292] Table 4B: Percentage of patients achieving ROM of 100°

[0293] Knee effusion

[0294] Fig. 7 is a graph showing the knee effusion (percentage difference in circumference from contralateral knee) versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (white circles) and patients administered MMA alone (black circles) for all patients (top panel) or only those patients who have not previously had a TKR (bottom panel). Statistically significant improvement in joint effusion was demonstrated in patient randomized to F14 compared to MMA at 6 weeks (p=0.003), 3 months (p=0.020), and 12 months (p=0.023). While not statistically different, numerical improvement was observed at 2 weeks in patients randomized to F14, see full results set out in Table 5 below.

[0295] Table 5: Timed-Up-and-Go Test (TUG)

[0296] Fig. 8 is a graph showing the Timed-Up-and-Go Test (TUG) duration versus time for patients administered the F14 formulation in combination with standardized multimodal analgesia (MMA) (squares) and patients administered MMA alone (circles) for all patients (top panel) or only those patients who have not previously had a TKR (bottom panel).

[0297] Table 6 below provides TUG values for all patients and patients with no previous TKR.

[0298] Table 6: Timed-Up-and-Go Test

[0299] Patients with no previous TKR randomized to F14 demonstrated substantially shorter times to complete the test, approaching statistical significance at 2 weeks, and significantly shorter at 6 weeks and 3 months.

[0300] Time to Return to Work

[0301] More patients who received formulation F14 and MMA had returned to work by 3 months after surgery than patients who received only MMA, with the population of patients who had not previously had a TKR having an even greater proportion returning to work by 3 months, see Table 7:

[0302] Table 7: Time to Return to Work SF-12 v2 (short form health survey)

[0303] The SF-12 is a validated, self-reported outcome measure assessing the impact of physical and mental health on individuals’ everyday life. It is often used as a quality of life measure. Patients receiving formulation F14 and MMA scored numerically better than patients who received only the MMA on all 8 domains of the questionnaire at each time-point. Table 8 below shows the domains of Physical Functioning and Table 9 the composite score, Physical Component Summary (PCS):

[0304] Table 8: SF-12 Survey Results

[0305] Physical Functioning Health Domain

[0306] Table 9: SF-12 Survey Results PCS score

[0307] At 3 months post-surgery, the patients receiving formulation F14 and MMA showed substantial improvement for all Domains, and both the PCS and the composite score Mental Component Summary (MCS) as shown in Table 10: Table 10: SF-12 Survey Results at 3 months EQ-5D-5L

[0308] EQ-5D is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. A negative result indicates worsening from baseline. Values are provided for all patients and for patients with no previous TKR in Table 11 below. The negative values for patients who received only MMA at 2 weeks indicates a worsening from baseline, compared to patients receiving formulation F14 and MMA who were improved over their baseline scores.

[0309] Table 11: EQ-5D-5L Index Value

[0310] Knee Society Score 2011 (KSS2011)

[0311] The KSS2011 is a validated, reliable tool with both objective and subjective scales (4 total), see Noble PC, Scuderi GR, Brekke AC, Sikorskii A, Benjamin JB, Lonner JH, Chadha P, Daylamani DA, Scott WN, Bourne RB. Development of a New Knee Society Scoring System. Clin Orthop Relat Res. 2011. It is one of the most often used methods to evaluate TKR patients. It is a validated system that combines an objective physician-derived component with a patient-derived component that evaluates pain relief, functional abilities, satisfaction, and fulfillment of expectations. The results are provided in Table 12 below for all patients, and for patients with no previous TKR. Table 12: Knee Society Score 2011 (KSS2011) Results

[0312] ALL TKR

[0313] NO TKR Domains “Objective Knee Indicators” and “Patient Expectations” were equivalent between groups. Comparative analysis was conducted for Change from Screening.

[0314] While the study failed to meet statistical significance regarding its primary endpoint related to pain intensity, statistically significant improvement in outcomes related to inflammation (e.g., knee ROM, joint effusion) was demonstrated at both 6 weeks and 3 months after surgery which has implications for patients in regard to the speed at which they may regain function and return to normal daily activities. Numerical improvements were also identified at all timepoints for Timed Up and Go test, time to return to work at 3 months, the SF-12, EQ-5D and KSS2011 scores. Further, when considering the large subpopulation of patients in this study who had not had prior TKR, statistical significance was demonstrated in pain intensity at 3 days with numerical and consistent improvement in pain intensity at later time-points. Patients who had not had prior TKR and were randomized to F14 also demonstrated reduced opioid consumption and had additional improvement in knee ROM at all time-points measured, knee effusion, Timed up and go (significant at 6 weeks and 3 months), time to return to work, SF-12, EQ-5D and KSS2011 scores (significant at 2 weeks and 6 weeks for the Functional activity scale) . Finally, the study demonstrated the excellent safety and tolerability of F14 in patients receiving TKR compared to the active control group.

[0315] While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions and changes may be made without departing from the scope thereof. Accordingly, it is intended that the scope of the present invention be limited by the scope of the claims, including equivalents thereof.

Claims

CLAIMSWhat is claimed is:

1. A method for treating or managing pain or inflammation in a patient following a total knee replacement (TKR) which comprises administering to the knee joint of said patient a biodegradable drug delivery composition comprising:(a) a biodegradable triblock copolymer having the formula:PLAv-PEGw-PLAx wherein v and x are the number of repeat units ranging from 24 to 682 and w is the number of repeat units ranging from 4 to 273 and v=x or v x;(b) a biodegradable diblock copolymer having the formula: mPEGy-PLAz wherein y and z are the number of repeat units with y ranging from 3 to 68 and z ranging from 7 to 327, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 3:2 to 1 :19 in said biodegradable drug composition the and (c) a nonsteroidal antiinflammatory drug (NSAID).

2. The method according to Claim 1 , wherein said patient has not previously had TKR.

3. A method for treating or managing pain or inflammation in a patient following a TKR which comprises administering to the knee joint of said patient a biodegradable drug delivery composition comprising:(a) a biodegradable triblock copolymer having the formula:PLAv-PEGw-PLAx wherein v and x are the number of repeat units ranging from 24 to 682 and w is the number of repeat units ranging from 4 to 273 and v=x or v x;(b) a biodegradable diblock copolymer having the formula: mPEGy-PLAzwherein y are the number of repeat units with y ranging from 3 to 68 and z ranging from 7 to 327, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 3:2 to 1 :19 in said biodegradable drug composition the and (c) a nonsteroidal antiinflammatory drug (NSAID),wherein said patient has not previously had a TKR.

4. The method according to any one of Claims 1 to 3, wherein the NSAID is present in said composition in an amount of 1% to 85% w% / w%, 1% to 60% (wt% / wt%), or 10% to 60% (wt% / wt%), or 10% to 30% (wt% / wt%), or 10% to 20% (wt% / wt%), or about 15% (wt% / wt%) of the total composition.

5. The method according to any one of Claims 1 to 4, wherein the polyethylene glycol chain in the triblock copolymer and / or the diblock copolymer has a molecular weight ranging from 300 Da to 12 kDa, or 1 kDa to 8 kDa, or 1 kDa to 5 kDa, or 1 kDa to 2 kDa.

6. The method according to Claim 5, wherein the polyethylene glycol chain in the triblock and / or the diblock copolymer has a molecular weight of 1 .5 to 2.5 kDa, or about 2 kDa.

7. The method according to any one of claims 1 to 6 wherein the lactic acid to ethylene oxide molar ratio for the triblock copolymer is from 1 .6 to 7.2 or 1.6 to 5.0 or 1 .6 to 3.0, or about 2.0.

8. The method according to any one of claims 1 to 7 wherein the lactic acid to ethylene oxide molar ratio for the diblock copolymer is from 1 .6 to 7.2 or 1 .6 to 5.0 or 1.9 to 4.8, or 1.9 to 3.0, or about 2.4.

9. The method according to any one of Claims 1 to 8, wherein the lactic acid to ethylene oxide molar ratio is 1 .6 to 7.2 in the triblock copolymer and 1.9 to 4.8 in the diblock copolymer.

10. The method according to any one of Claims 1 to 9, wherein the degree of polymerization in the triblock copolymer is from 92 to 135 and the degree of polymerization in the diblock copolymer is from 91 to 180, or the degree of polymerization in the triblock copolymer is 95 to 130 and the degree of polymerization in the diblock copolymer is from 95 to 175, or the degree of polymerization in the triblock copolymer is 99 to 132 and the degree of polymerization in the diblock copolymer is from 95 to 175, or the degree of polymerization in the triblock copolymer is 100 to 170 and the degree of polymerization in the diblock copolymer is from 115 to 195.

11. The method according to any one of Claims 1 to 10, wherein the triblock copolymer is present in an amount of 2% to 45% (wt% / wt%), or 6% to 24% (wt% / wt%), or 6% to 15% (wt% / wt%), 6% to 10% (wt% / wt%), or about 8% (wt% / wt%) of the total composition.

12. The method according to any one of Claims 1 to 11 , wherein the diblock copolymer is present in an amount of 8% to 50% (wt% / wt%), or 12% to 40% (wt% / wt%), or 20% to 40% (wt% / wt%), or about 32% (wt% / wt%) of the total composition.

13. The method according to any one of Claims 1 to 12, wherein the triblock copolymer is present in an amount of 6% to 24% (wt% / wt%) and the diblock copolymer is present in an amount of 12% to 40% (wt% / wt%) of the total composition.

14. The method according to any one of Claims 1 to 13, wherein the total polymer content ranges from 20% to 50% (w% / w%) or 30% to 50% (w% / w%), or about 40% (w% / w%) of the total composition.

15. The method according to any one of Claims 1 to 14, wherein the total polymer content ranges from 30% to 50% (w% / w%) of the total composition and the NSAID is present in an amount of 10% to 20% (w% / w%) of the total composition.

16. The method to any one of Claims 1 to 15, further comprising a pharmaceutically acceptable vehicle.

17. The method according to claim 16, wherein the pharmaceutically acceptable vehicle is a biocompatible organic solvent.

18. The method according to claim 17, wherein the biocompatible organic solvent is selected from the group of: benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidinone(NMP), pyrrolidone-2, tetraglycol, triacetin, tributyrin, tripropionin (tripro) and mixtures thereof. In one embodiment the solvents are DMSO, tripo, NMP and mixtures thereof, optionally DMSO.

19. The method according to any one of claims 1 to 18, wherein the NSAID is at least one of etofenamate, celecoxib, apricoxib, rofecoxib, nabumetone, benorilate, etoricoxib, ampiroxicam, aminophemazone, valdecoxib, acetominophen, bufexamac, nimesulide, parecoxib, mefenamic acid, dexibuprofen, ibuprofen, flurbiprofen, aspirin, dexketoprofen, diclofenac, diflunisal, etodolac, fenoprofen, firocoxib, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, loxomac, lumiracoxib, meclofenamic acid, meloxicam, naproxen,naprosyn, nimalox, oxaporozin, piroxicam, salsalate, sulindac, tenoxicam, tolfenamic acid, and ropivicaine.

20. The method according to claim 19, wherein the NSAID is celecoxib.

21. The method according to claim 20, comprising celecoxib in an amount of 13% to 17% (wt% / wt%), the triblock copolymer in an amount of 7% to 9% (wt% / wt%), the diblock copolymer in an amount of 30% to 34% (wt% / wt%), and dimethyl sulfoxide in an amount of 43% to 47% (wt% / wt%) of the total composition.

22. The method according to any one of Claims 1 to 21 , wherein the formulation of said biodegradable drug composition is made by mixing the triblock copolymer with the diblock copolymer in a biocompatible organic solvent to form a triblock copolymer and diblock copolymer mixture, and the NSAID is added to said triblock copolymer and diblock copolymer mixture.

23. The method according to any one of Claims 1 to 22, wherein the composition is administered to said patient in a volume of 0.1 to 6 mL or 2 to 5 mL or 3 to 4 mL.

24. The method according to any one of claims 20 to 23 wherein the composition has a concentration of celecoxib of from about 150 mg / mL to about 200 mg / mL, or from about 170 to about 190 mg / mL.

25. The method according to claim 24 wherein the maximal celecoxib plasmatic concentration reached after a single administration of the composition is less than 200 ng / mL, optionally less than 180 ng / mL, optionally less than 160 ng / mL 24 hours after the TKR.

26. The method according to any one of claims 1 to 25 wherein a therapeutically effective concentration of the NSAID is released for a period of at least 4 weeks, preferably at least 6 weeks after the TKR.

27. The method according to any one of Claims 1 to 26, wherein said composition is a liquid that can be injected into the knee joint or are solid particles that can be injected into the knee joint or are rod implants or spatial formulations.

28. The method according to any one of claims 1 to 27, wherein the method further comprises the administration of standardized multimodal analgesia.

29. The method according to claim 28 wherein the standardized multimodal analgesia comprises two or more active pharmaceutical ingredients selected from bupivacaine, ropivacaine, lidocaine, acetaminophen, methocarbamol, pregabalin, gabapentin, ketamine, morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, tramadol, tapentadol, a nerve block and dexamethasone; or wherein the standardized multimodal analgesia comprises bupivacaine hydrochloride, acetaminophen and methocarbamol.

30. The method according to claim 29, wherein bupivacaine is administered via periarticular infiltration using a mixture of 0.25% bupivacaine with epinephrine (1 :200,000) and 0.25% bupivacaine without epinephrine at a ratio of 2:1 respectively for subjects weighing less than 80 kg, and at a ratio of 3:1 respectively for subjects weighing more than 80 kg at 1 mL / kg up to 90 mL.

31. The method according to any one of claims 28 to 30 wherein the standardized multimodal analgesia comprises an opioid, optionally wherein the opioid is selected from morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, tramadol, tapentadol and combinations thereof or wherein the opioid is morphine and / or oxycodone.

32. The method according to claim 31 wherein the daily opioid consumption or mean cumulative opioid consumption of the patient is reduced relative to a patient receiving only the standardized multimodal analgesia comprising opioid, optionally wherein opioid consumption is reduced from 2 weeks to 90 days after the TKR, or over 2 weeks, or 4 weeks or 6 weeks, or 8 weeks or 12 weeks, or 90 days after the TKR; or there is from 15% to 20% reduction in cumulative opioid consumption 90 days after the TKR; or for patients who have had no previous TKR, there is from a 25% to 30% reduction in cumulative opioid consumption 90 days after the TKR.

33. The method according to any one of claims 1 to 32, wherein is a reduction in Area Under the Curve (AUC) of Numeric Rating Score (NRS) pain of the patient at 3 days, 7 days, 2 weeks, 6 weeks or 90 days after the TKR relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the reduction is calculated based on the least squares mean of AUC of NRS; or there is a reduction in least squares mean of AUC of NRS pain of the patient relative to a patient receiving only the standardized multimodal analgesia of at least 3%, optionally least 4%, optionally at least 5%, optionally at least 6%; or for patients with no previous TKR, there is a reduction in least squares mean of AUC of NRS pain of the patient relative to a patient receiving only the standardized multimodal analgesia of at least8%, optionally at least 9%, optionally at least 10%, optionally at least 12%, optionally at least 14%, optionally at least 16%.

34. The method of claim 33, wherein the AUC of Numeric Rating Score (NRS) pain is adjusted for consumption of opioids.

35. The method according to any one of claims 1 to 34, wherein there is a reduction in the least squares mean of the Visual Analog Scale (VAS) for pain of the patient at 2 weeks, 6 weeks or 90 days after the TKR relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the reduction is at least an 10%, optionally at least a 20% difference in least squares mean of the VAS.

36. The method according to any one of claims 1 to 35 wherein the patient has a reduced time period to a knee range of motion of between 100 and 110 degrees relative to a patient receiving only the standardized multimodal analgesia.

37. The method according to any one of claims 1 to 36 wherein the patient has an improved knee range of motion relative to a patient receiving only the standardized multimodal analgesia between 1 week and 3 months after the TKR or at 1 week, or at 2 weeks, or at 3 weeks, or at 6 weeks, or at 12 weeks after the TKR, optionally wherein there is a 5 to 10% improvement of ROM relative to a patient receiving only the standardized multimodal analgesia at 3 months after the TKR.

38. The method according to any one of claims 1 to 37 wherein there is a reduction in effusion of the knee of the patient measured as the percentage difference in circumference of the knee which has had a TKR relative to the contralateral knee and relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the measurement is made at 2 weeks, or at 6 weeks or at 3 months after the TKR.

39. The method according to any one of claims 1 to 38 wherein there is an improvement in mobility of the patient as measured by the Timed Up and Go Test relative to a patient receiving only the standardized multimodal analgesia, wherein the Timed Up and Go Test measures the time it takes for the patient to stand up, walk a distance of 3 meters (10 feet), turn, walk back and sit down again, optionally wherein the Timed Up and Go Test result is measured at 2 weeks or at 6 weeks or at 3 months after the TKR.

40. The method according to any one of claims 1 to 39 wherein the Physical Component Summary score of the Short Form 12 (SF-12v2) Health Survey is increased by at least 15% or at least 30% from the value for a patient receiving only the standardized multimodal analgesia.

41. The method according to any one of claims 1 to 40 wherein the health status of a patient as measured by the EuroQoL 5D (EQ-5D-5L) index 2 weeks after the TKR is improved relative to a patient receiving only the standardized multimodal analgesia, optionally wherein the index increases by at least 70, or at least 85 from the value for a patient receiving only the standardized multimodal analgesia; or where patients have not had a previous TKR, the index 2 weeks after the TKR increases by at least 150, or at least 170 from the value for a patient receiving only the standardized multimodal analgesia.

42. The method according to any one of claims 1 to 41 wherein the Knee Society Score 2011 (KSS2011) of a patient as measured 2 weeks after the TKR is improved relative to a patient receiving only the standardized multimodal analgesia, optionally wherein there is at least a 30%, or at least a 40%, or at least a 50% increase in the KSS2011 patient satisfaction and / or functional activities score of a patient relative to a patient receiving only the standardized multimodal analgesia; or for patients who have not previously had a TKR, there is at least a 40%, or at least a 50%, or at least a 60% increase in the KSS2011 patient satisfaction and / or functional activities score of a patient relative to a patient receiving only the standardized multimodal analgesia.

43. The method according to any one of Claims 1 to 42, wherein said biodegradable drug delivery composition is taken up by syringe for administration and injected into said knee joint or manually formed into a solid bolus by exposing the composition to aqueous liquid and manual placement into the knee joint.

44. The method according to any one of claims 1 to 43, wherein said biodegradable drug delivery composition is subjected to a mechanical challenge.

45. The method according to Claim 44, wherein said mechanical challenge is obtained by internal structures of the joints, articulation, weight bearing and / or by synovial fluid pressure.

46. A composition for use in a method as defined in any one of claims 1 to 45.

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